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1.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
doi:10.1038/ng.3014
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
2.  Caffeine Consumption Contributes to Skin Intrinsic Fluorescence in Type 1 Diabetes 
Diabetes Technology & Therapeutics  2015;17(10):726-734.
Abstract
Background: A variant (rs1495741) in the gene for the N-acetyltransferase 2 (NAT2) protein is associated with skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation end products and other fluorophores in the skin. Because NAT2 is involved in caffeine metabolism, we aimed to determine whether caffeine consumption is associated with SIF and whether rs1495741 is associated with SIF independently of caffeine.
Materials and Methods: SIF was measured in 1,181 participants with type 1 diabetes from the Epidemiology of Diabetes Interventions and Complications study. Two measures of SIF were used: SIF1, using a 375-nm excitation light-emitting diode (LED), and SIF14 (456-nm LED). Food frequency questionnaires were used to estimate mean caffeine intake. To establish replication, we examined a second type 1 diabetes cohort.
Results: Higher caffeine intake was significantly associated with higher SIF1LED 375 nm[0.6, 0.2] (P=2×10−32) and SIF14LED 456 nm[0.4, 0.8] (P=7×10−31) and accounted for 4% of the variance in each after adjusting for covariates. When analyzed together, caffeine intake and rs1495741 both remained highly significantly associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8]. Mean caffeinated coffee intake was also positively associated with SIF1LED 375 nm[0.6, 0.2] (P=9×10−12) and SIF14LED 456 nm[0.4, 0.8] (P=4×10−12), but no association was observed for decaffeinated coffee intake. Finally, caffeine was also positively associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8] (P<0.0001) in the replication cohort.
Conclusions: Caffeine contributes to SIF. The effect of rs1495741 on SIF appears to be partially independent of caffeine consumption. Because SIF and coffee intake are each associated with cardiovascular disease, our findings suggest that accounting for coffee and/or caffeine intake may improve risk prediction models for SIF and cardiovascular disease in individuals with diabetes.
doi:10.1089/dia.2015.0017
PMCID: PMC4575521  PMID: 26192006
3.  GRIN1 polymorphisms do not affect susceptibility or phenotype in NMDA receptor encephalitis 
Objective:
To determine whether distinct single nucleotide polymorphisms (SNPs) within the glutamate receptor ionotropic NMDA 1 gene (GRIN1) are associated with NMDA receptor (NMDAR) encephalitis and whether these same variants are associated with variability in the clinical presentation and course of affected patients.
Methods:
We performed clinical follow-up on 48 patients with NMDAR encephalitis and NMDAR autoantibodies detected in serum or CSF. All RefSeq GRIN1 coding exons were sequenced in 39 Caucasian-European patients, and the frequencies of SNPs were compared with those of an ethnically similar population using a case-control study design. Predetermined clinical variables were compared between patients with and without identified SNPs.
Results:
Two SNPs were identified in GRIN1: 24 (62%) Caucasian-European patients with NMDAR encephalitis had alternate alleles at both rs6293 (exon 6) and rs1126442 (exon 7; exon numbering according to NM_001185090). The SNPs were in complete linkage disequilibrium. The frequency of these variants did not differ between patients with NMDAR encephalitis and ethnically matched individuals in the general population. No differences in clinical presentation, measures of disease severity, clinical course, or outcomes were observed between patients with different genotypes at these SNPs.
Conclusion:
Disease susceptibility or course in patients with NMDAR encephalitis was not strongly affected by SNPs in GRIN1. This study provides an estimate of the frequency of SNPs in GRIN1 in patients with NMDAR encephalitis and emphasizes the need for multisite collaborative studies enrolling larger numbers of patients to identify the genetic contributions to NMDAR encephalitis.
doi:10.1212/NXI.0000000000000153
PMCID: PMC4582904  PMID: 26443875
4.  Assessment and Selection of Competing Models for Zero-Inflated Microbiome Data 
PLoS ONE  2015;10(7):e0129606.
Typical data in a microbiome study consist of the operational taxonomic unit (OTU) counts that have the characteristic of excess zeros, which are often ignored by investigators. In this paper, we compare the performance of different competing methods to model data with zero inflated features through extensive simulations and application to a microbiome study. These methods include standard parametric and non-parametric models, hurdle models, and zero inflated models. We examine varying degrees of zero inflation, with or without dispersion in the count component, as well as different magnitude and direction of the covariate effect on structural zeros and the count components. We focus on the assessment of type I error, power to detect the overall covariate effect, measures of model fit, and bias and effectiveness of parameter estimations. We also evaluate the abilities of model selection strategies using Akaike information criterion (AIC) or Vuong test to identify the correct model. The simulation studies show that hurdle and zero inflated models have well controlled type I errors, higher power, better goodness of fit measures, and are more accurate and efficient in the parameter estimation. Besides that, the hurdle models have similar goodness of fit and parameter estimation for the count component as their corresponding zero inflated models. However, the estimation and interpretation of the parameters for the zero components differs, and hurdle models are more stable when structural zeros are absent. We then discuss the model selection strategy for zero inflated data and implement it in a gut microbiome study of > 400 independent subjects.
doi:10.1371/journal.pone.0129606
PMCID: PMC4493133  PMID: 26148172
5.  Assessing models for genetic prediction of complex traits: a comparison of visualization and quantitative methods 
BMC Genomics  2015;16(1):405.
Background
In silico models have recently been created in order to predict which genetic variants are more likely to contribute to the risk of a complex trait given their functional characteristics. However, there has been no comprehensive review as to which type of predictive accuracy measures and data visualization techniques are most useful for assessing these models.
Methods
We assessed the performance of the models for predicting risk using various methodologies, some of which include: receiver operating characteristic (ROC) curves, histograms of classification probability, and the novel use of the quantile-quantile plot. These measures have variable interpretability depending on factors such as whether the dataset is balanced in terms of numbers of genetic variants classified as risk variants versus those that are not.
Results
We conclude that the area under the curve (AUC) is a suitable starting place, and for models with similar AUCs, violin plots are particularly useful for examining the distribution of the risk scores.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1616-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1616-z
PMCID: PMC4440290  PMID: 25997848
Predictive accuracy; Genetic prediction; Receiver operating characteristic curve
6.  Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes 
Lionel, Anath C. | Tammimies, Kristiina | Vaags, Andrea K. | Rosenfeld, Jill A. | Ahn, Joo Wook | Merico, Daniele | Noor, Abdul | Runke, Cassandra K. | Pillalamarri, Vamsee K. | Carter, Melissa T. | Gazzellone, Matthew J. | Thiruvahindrapuram, Bhooma | Fagerberg, Christina | Laulund, Lone W. | Pellecchia, Giovanna | Lamoureux, Sylvia | Deshpande, Charu | Clayton-Smith, Jill | White, Ann C. | Leather, Susan | Trounce, John | Melanie Bedford, H. | Hatchwell, Eli | Eis, Peggy S. | Yuen, Ryan K.C. | Walker, Susan | Uddin, Mohammed | Geraghty, Michael T. | Nikkel, Sarah M. | Tomiak, Eva M. | Fernandez, Bridget A. | Soreni, Noam | Crosbie, Jennifer | Arnold, Paul D. | Schachar, Russell J. | Roberts, Wendy | Paterson, Andrew D. | So, Joyce | Szatmari, Peter | Chrysler, Christina | Woodbury-Smith, Marc | Brian Lowry, R. | Zwaigenbaum, Lonnie | Mandyam, Divya | Wei, John | MacDonald, Jeffrey R. | Howe, Jennifer L. | Nalpathamkalam, Thomas | Wang, Zhuozhi | Tolson, Daniel | Cobb, David S. | Wilks, Timothy M. | Sorensen, Mark J. | Bader, Patricia I. | An, Yu | Wu, Bai-Lin | Musumeci, Sebastiano Antonino | Romano, Corrado | Postorivo, Diana | Nardone, Anna M. | Monica, Matteo Della | Scarano, Gioacchino | Zoccante, Leonardo | Novara, Francesca | Zuffardi, Orsetta | Ciccone, Roberto | Antona, Vincenzo | Carella, Massimo | Zelante, Leopoldo | Cavalli, Pietro | Poggiani, Carlo | Cavallari, Ugo | Argiropoulos, Bob | Chernos, Judy | Brasch-Andersen, Charlotte | Speevak, Marsha | Fichera, Marco | Ogilvie, Caroline Mackie | Shen, Yiping | Hodge, Jennelle C. | Talkowski, Michael E. | Stavropoulos, Dimitri J. | Marshall, Christian R. | Scherer, Stephen W.
Human Molecular Genetics  2013;23(10):2752-2768.
Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3′ terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3′-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3′ end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
doi:10.1093/hmg/ddt669
PMCID: PMC3990173  PMID: 24381304
7.  Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk 
Nature communications  2014;5:5303.
Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci.
doi:10.1038/ncomms6303
PMCID: PMC4320806  PMID: 25342443
8.  Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci 
PLoS ONE  2014;9(9):e107110.
Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10−8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10−11) and 8q12 (minimum p value 1.82×10−11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. “Replication-level” association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.
doi:10.1371/journal.pone.0107110
PMCID: PMC4169415  PMID: 25233373
9.  Haptoglobin Genotype and the Rate of Renal Function Decline in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes  2013;62(9):3218-3223.
Many patients with type 1 diabetes develop renal disease despite moderately good metabolic control, suggesting other risk factors may play a role. Recent evidence suggests that the haptoglobin (HP) 2-2 genotype, which codes for a protein with reduced antioxidant activity, may predict renal function decline in type 1 diabetes. We examined this hypothesis in 1,303 Caucasian participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. HP genotype was determined by polyacrylamide gel electrophoresis. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and albumin excretion based on timed urine samples. Participants were followed up for a mean of 22 years. HP genotype was significantly associated with the development of sustained estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m2 and with end-stage renal disease (ESRD), with HP 2-2 having greater risk than HP 2-1 and 1-1. No association was seen with albuminuria. Although there was no treatment group interaction, the associations were only significant in the conventional treatment group, where events rates were much higher. We conclude that the HP genotype is significantly associated with the development of reduced GFR and ESRD in the DCCT/EDIC study.
doi:10.2337/db13-0256
PMCID: PMC3749329  PMID: 23761102
10.  Germline Mutation of RPS20, Encoding a Ribosomal Protein, Causes Predisposition to Hereditary Nonpolyposis Colorectal Carcinoma Without DNA Mismatch Repair Deficiency 
Gastroenterology  2014;147(3):595-598.e5.
Little is known about the genetic factors that contribute to familial colorectal cancer type X (FCCX), characterized by hereditary nonpolyposis colorectal carcinoma with no mismatch repair defects. Genetic linkage analysis, exome sequencing, tumor studies, and functional investigations of 4 generations of a FCCX family led to the identification of a truncating germline mutation in RPS20, which encodes a component (S20) of the small ribosomal subunit and is a new colon cancer predisposition gene. The mutation was associated with a defect in pre–ribosomal RNA maturation. Our findings show that mutations in a gene encoding a ribosomal protein can predispose individuals to microsatellite-stable colon cancer. Evaluation of additional FCCX families for mutations in RPS20 and other ribosome-associated genes is warranted.
doi:10.1053/j.gastro.2014.06.009
PMCID: PMC4155505  PMID: 24941021
Colon Cancer; Hereditary Nonpolyposis Colorectal Cancer; Ribosome; Exome Sequencing; FCCX, hereditary nonpolyposis colorectal cancer type X; rRNA, ribosomal RNA
11.  Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error 
Human Molecular Genetics  2013;22(13):2754-2764.
Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (‘Cooperative Health Research in the Region of Augsburg’); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10−9) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.
doi:10.1093/hmg/ddt116
PMCID: PMC3674806  PMID: 23474815
12.  GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence 
Diabetologia  2014;57(8):1623-1634.
Aims/hypothesis
Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts.
Methods
Cohort 1 included 1,082 participants, 35–67 years of age with type 1 diabetes. Cohort 2 included 8,721 participants without diabetes, aged 18–90 years.
Results
rs1495741 was significantly associated with SF in Cohort 1 (p < 6 × 10−10), which is known to tag the NAT2 acetylator phenotype. The fast acetylator genotype was associated with lower SF, explaining up to 15% of the variance. In Cohort 2, the top signal associated with SF (p = 8.3 × 10−42) was rs4921914, also in NAT2, 440 bases upstream of rs1495741 (linkage disequilibrium r2 = 1.0 for rs4921914 with rs1495741). We replicated these results in two additional cohorts, one with and one without type 1 diabetes. Finally, to understand which compounds are contributing to the NAT2–SF signal, we examined 11 compounds assayed from skin biopsies (n = 198): the fast acetylator genotype was associated with lower levels of the AGEs hydroimidazolones of glyoxal (p = 0.017).
Conclusions/interpretation
We identified a robust association between NAT2 and SF in people with and without diabetes. Our findings provide proof of principle that genetic variation contributes to interindividual SF and that NAT2 acetylation status plays a major role.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3286-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-014-3286-9
PMCID: PMC4079945  PMID: 24934506
Acetylation; Genome-wide association study; NAT2; Skin autofluorescence; Skin fluorescence; Skin intrinsic fluorescence
13.  Using a Bayesian latent variable approach to detect pleiotropy in the Genetic Analysis Workshop 18 data 
BMC Proceedings  2014;8(Suppl 1):S77.
Pleiotropy, which occurs when a single genetic factor influences multiple phenotypes, is present in many genetic studies of complex human traits. Longitudinal family data, such as the Genetic Analysis Workshop 18 data, combine the features of longitudinal studies in individuals and cross-sectional studies in families, thus providing richer information about the genetic and environmental factors associated with the trait of interest. We recently proposed a Bayesian latent variable methodology for the study of pleiotropy, in the presence of longitudinal and family correlation. The purpose of this work is to evaluate the Bayesian latent variable method in a real data setting using the Genetic Analysis Workshop 18 blood pressure phenotypes and sequenced genotype data. To detect single-nucleotide polymorphisms with pleiotropic effect on both diastolic and systolic blood pressure, we focused on a set of 6 single-nucleotide polymorphisms from chromosome 3 that was reported in the literature to be significantly associated with either diastolic blood pressure or the binary hypertension trait. Our analysis suggests that both diastolic blood pressure and systolic blood pressure are associated with the latent hypertension severity variable, but the analysis did not find any of the 6 single-nucleotide polymorphisms to have statistically significant pleiotropic effect on both diastolic blood pressure and systolic blood pressure.
doi:10.1186/1753-6561-8-S1-S77
PMCID: PMC4143687  PMID: 25519405
14.  Evaluation of gene-based association tests for analyzing rare variants using Genetic Analysis Workshop 18 data 
BMC Proceedings  2014;8(Suppl 1):S9.
The focus of our work is to evaluate several recently developed pooled association tests for rare variants and assess the impact of different gene annotation methods and binning strategies on the analyses of rare variants under Genetic Analysis Workshop 18 real and simulated data settings. We considered the sample of 103 unrelated individuals with sequence data, genotypes of rare variants from chromosome 3, real phenotype of hypertension status and simulated phenotypes of systolic blood pressure (SBP) and diastolic blood pressure (DBP), and covariates of age, sex, and the interaction between age and sex. In the analysis of real phenotype data, we did not obtain significant results for any binning strategy; however, we observed a slight deviation of the p-values from the uniform distribution based on the protein-damaging variant grouping strategy. Evaluation of methods using simulated data showed lack of power even at the conservative level of 0.05 for most of the causal genes on chromosome 3. Nevertheless, analysis of MAP4 produced good power for all tests at various levels of the tests for both DBP and SBP. Our results also confirmed that Fisher's method is not only robust but can also improve power over individual pooled linear and quadratic tests and is often better than other robust tests such as SKAT-O.
doi:10.1186/1753-6561-8-S1-S9
PMCID: PMC4143759  PMID: 25519417
15.  Dynamic pathway analysis of genes associated with blood pressure using whole genome sequence data 
BMC Proceedings  2014;8(Suppl 1):S106.
Groups of genes assigned to a pathway, also called a module, have similar functions. Finding such modules, and the topology of the changes of the modules over time, is a fundamental problem in understanding the mechanisms of complex diseases. Here we investigated an approach that categorized variants into rare or common and used a hierarchical model to jointly estimate the group effects of the variants in a pathway for identifying enriched pathways over time using whole genome sequencing data and blood pressure data. Our results suggest that the method can identify potentially biologically meaningful genes in modules associated with blood pressure over time.
doi:10.1186/1753-6561-8-S1-S106
PMCID: PMC4143637  PMID: 25519360
16.  Genetic Analysis Workshop 18 single-nucleotide variant prioritization based on protein impact, sequence conservation, and gene annotation 
BMC Proceedings  2014;8(Suppl 1):S11.
Grouping variants based on gene mapping can augment the power of rare variant association tests. Weighting or sorting variants based on their expected functional impact can provide additional benefit. We defined groups of prioritized variants based on systematic annotation of Genetic Analysis Workshop 18 (GAW18) single-nucleotide variants; we focused on variants detected by whole genome sequencing, specifically on the high-quality subset presented in the genotype files. First, we divided variants between coding and noncoding. Coding variants are fewer than 1% of the total and are more likely to have a biological effect than noncoding variants. Coding variants were further stratified into protein changing and protein damaging groups based on the effect on protein amino acid sequence. In particular, missense variants predicted to be damaging, splice-site alterations, and stop gains were assigned to the protein damaging category. Impact of noncoding variants is more difficult to predict. We decided to rely uniquely on conservation: we combined (a) the mammalian phastCons Conserved Element and (b) the PhyloP score, which identify conserved intervals and the single-nucleotide position, respectively. This reduced the noncoding variants to a number comparable to coding variants. Finally, using gene structure definition from the widely used RefSeq database, we mapped variants to genes to support association tests that require collapsing rare variants to genes. Companion GAW18 papers used these variant priority groups and gene mapping; one of these paper specifically found evidence of stronger association signal for protein damaging variants.
doi:10.1186/1753-6561-8-S1-S11
PMCID: PMC4143669  PMID: 25519362
17.  A Novel Susceptibility Locus on Rat Chromosome 8 Affects Spontaneous but Not Experimentally Induced Type 1 Diabetes 
Diabetes  2007;56(6):1731-1736.
OBJECTIVE
The biobreeding diabetes-prone (BBDP) rat spontaneously develops type 1 diabetes. Two of the genetic factors contributing to this syndrome are the major histocompatibility complex (Iddm1) and a Gimap5 mutation (Iddm2) responsible for a T-lymphopenia. Susceptibility to experimentally induced type 1 diabetes is widespread among nonlymphopenic (wild-type Iddm2) rat strains provided they share the BBDP Iddm1 allele. The question follows as to whether spontaneous and experimentally induced type 1 diabetes share susceptibility loci besides Iddm1. Our objectives were to map a novel, serendipitously discovered Iddm locus, confirm its effects by developing congenic sublines, and assess its differential contribution to spontaneous and experimentally induced type 1 diabetes.
RESEARCH DESIGN AND METHODS
An unexpected reduction in spontaneous type 1 diabetes incidence (86 to 31%, P < 0.0001) was observed in a BBDP line congenic for a Wistar Furth–derived allotypic marker, RT7 (chromosome 13). Genome-wide analysis revealed that, besides the RT7 locus, a Wistar Furth chromosome 8 fragment had also been introduced. The contribution of these intervals to diabetes resistance was assessed through linkage analysis using 134 F2 (BBDP × double congenic line) animals and a panel of congenic sublines. One of these sublines, resistant to spontaneous type 1 diabetes, was tested for susceptibility to experimentally induced type 1 diabetes.
RESULTS
Both linkage analysis and congenic sublines mapped a novel locus (Iddm24) to the telomeric 10.34 Mb of chromosome 8, influencing cumulative incidence and age of onset of spontaneous type 1 diabetes but not insulitis nor experimentally induced type 1 diabetes.
CONCLUSIONS
This study has identified a type 1 diabetes susceptibility locus that appears to act after the development of insulitis and that regulates spontaneous type 1 diabetes exclusively.
doi:10.2337/db06-1790
PMCID: PMC3987115  PMID: 17389329
18.  Genome-wide Linkage Analyses of Quantitative and Categorical Autism Subphenotypes 
Biological Psychiatry  2008;64(7):561-570.
Background
The search for susceptibility genes in autism and autism spectrum disorders (ASD) has been hindered by the possible small effects of individual genes and by genetic (locus) heterogeneity. To overcome these obstacles, one method is to use autism-related subphenotypes instead of the categorical diagnosis of autism since they may be more directly related to the underlying susceptibility loci. Another strategy is to analyze subsets of families that meet certain clinical criteria to reduce genetic heterogeneity.
Methods
In this study, using 976 multiplex families from the Autism Genome Project consortium, we performed genome-wide linkage analyses on two quantitative subphenotypes, the total scores of the reciprocal social interaction domain and the restricted, repetitive, and stereotyped patterns of behavior domain from the Autism Diagnostic Interview-Revised. We also selected subsets of ASD families based on four binary subphenotypes, delayed onset of first words, delayed onset of first phrases, verbal status, and IQ ≥ 70.
Results
When the ASD families with IQ ≥ 70 were used, a logarithm of odds (LOD) score of 4.01 was obtained on chromosome 15q13.3-q14, which was previously linked to schizophrenia. We also obtained a LOD score of 3.40 on chromosome 11p15.4-p15.3 using the ASD families with delayed onset of first phrases. No significant evidence for linkage was obtained for the two quantitative traits.
Conclusions
This study demonstrates that selection of informative subphenotypes to define a homogeneous set of ASD families could be very important in detecting the susceptibility loci in autism.
doi:10.1016/j.biopsych.2008.05.023
PMCID: PMC2670970  PMID: 18632090
Autism; genetic heterogeneity; IQ; language; linkage analysis; schizophrenia
19.  ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption  
The Journal of Clinical Investigation  2013;123(12):5179-5189.
Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.
doi:10.1172/JCI69000
PMCID: PMC3859425  PMID: 24270420
20.  Evaluating outlier loci and their effect on the identification of pedigree errors 
BMC Genetics  2005;6(Suppl 1):S155.
Homozygosity outlier loci, which show patterns of variation that are extremely divergent from the rest of the genome, can be evaluated by comparison of the homozygosity under Hardy-Weinberg proportions (the sum of the squares of allele frequencies) with the expected homozygosity under neutrality. Such outlier loci are potentially under selection (balancing selection or directional selection) when genome-wide effects (such as bottleneck and rapid population growth) are excluded. Outlier loci show skewed allele frequencies with respect to neutrality and may therefore affect the identification of pedigree errors. However, choosing neutral markers (excluding outlier loci) for the identification of pedigree errors has been neglected thus far. Our results showed that 4.1%, 5.5%, and 1.5% of the microsatellite markers, Illumina single-nucleotide polymorphisms (SNPs), and Affymetrix SNPs, respectively, on the autosomes appear to be under balancing selection (p ≤ 0.01) while 0.8% of the Affymetrix SNPs are consistent with directional selection. On the X-chromosome, 7.7%, 3.2%, and 0.4% of the microsatellite markers, Illumina SNPs, and Affymetrix SNPs, respectively, appear to be under balancing selection. 9.3% of Illumina SNPs and 6.7% of Affymetrix SNPs which have high minor allele frequency (≥40%) appear to be under balancing selection. Pedigree structure errors in 15 of 143 pedigrees were detected using microsatellite markers from the autosomes and/or selected SNPs from chromosomes 1 to 18 of the Illumina and/or selected SNPs from chromosomes 1 to 16 of the Affymetrix. Outlier loci did not make a major difference to the identification of pedigree errors. The Collaborative Study on the Genetics of Alcoholism data has pedigree errors and some of them may be due to sample mix up.
doi:10.1186/1471-2156-6-S1-S155
PMCID: PMC1866779  PMID: 16451616
22.  An analysis of identical single-nucleotide polymorphisms genotyped by two different platforms 
BMC Genetics  2005;6(Suppl 1):S152.
The overlap of 94 single-nucleotide polymorphisms (SNP) among the 4,720 and 11,120 SNPs contained in the linkage panels of Illumina and Affymetrix, respectively, allows an assessment of the discrepancy rate produced by these two platforms. Although the no-call rate for the Affymetrix platform is approximately 8.6 times greater than for the Illumina platform, when both platforms make a genotypic call, the agreement is an impressive 99.85%. To determine if disputed genotypes can be resolved without sequencing, we studied recombination in the region of the discrepancy for the most discrepant SNP rs958883 (typed by Illumina) and tsc02060848 (typed by Affymetrix). We find that the number of inferred recombinants is substantially higher for the Affymetrix genotypes compared to the Illumina genotypes. We illustrate this with pedigree 10043, in which 3 of 7 versus 0 of 7 offspring must be double recombinants using the genotypes from the Affymetrix and the Illumina platforms, respectively. Of the 36 SNPs with one or more discrepancies, we identified a subset that appears to cluster in families. Some of this clustering may be due to the presence of a second segregating SNP that obliterates a XbaI site (the restriction enzyme used in the Affymetrix platform), resulting in a fragment too long (>1,000 bp) to be amplified.
doi:10.1186/1471-2156-6-S1-S152
PMCID: PMC1866782  PMID: 16451613
23.  A genome scan for parent-of-origin linkage effects in alcoholism 
BMC Genetics  2005;6(Suppl 1):S160.
Background
Alcoholism is a complex disease in which genomic imprinting may play an important role in its susceptibility.
Objective
To conduct a genome-wide search for loci that may have strong parent-of-origin linkage effects in alcoholism; to compare the linkage results between the microsatellites and the two single-nucleotide polymorphism (SNP) platforms.
Methods
Nonparametric linkage analyses were performed using ALLEGRO with the three sets of markers provided by the Genetic Analysis Workshop 14 for the Collaborative Study on the Genetics of Alcoholism Problem 1 data. Both sex-averaged and sex-specific genetic maps were used. We also provided a valid statistical test to determine whether the parental allele sharing differed significantly.
Results
Significant maternal linkage effects (paternal imprinting) were observed on chromosome 12 using either the microsatellite markers or the two SNP panels. The two SNP sets did not improve the linkage signals compared to the results from the microsatellite markers on chromosome 12. Possible paternal linkage effects (maternal imprinting) on chromosome 7 and maternal linkage effects (paternal imprinting) on chromosome 10 were found using the two SNP panels.
Conclusion
For diseases which may have parent-of-origin effects, linkage analysis looking at parental sharing separately may reduce locus heterogeneity and increase the ability to identify that which can not be identified with usual linkage analysis.
doi:10.1186/1471-2156-6-S1-S160
PMCID: PMC1866773  PMID: 16451622
24.  NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2 
Gut  2011;61(7):1028-1035.
Objective
The NOX2 NADPH oxidase complex produces reactive oxygen species and plays a critical role in the killing of microbes by phagocytes. Genetic mutations in genes encoding components of the complex result in both X-linked and autosomal recessive forms of chronic granulomatous disease (CGD). Patients with CGD often develop intestinal inflammation that is histologically similar to Crohn's colitis, suggesting a common aetiology for both diseases. The aim of this study is to determine if polymorphisms in NOX2 NADPH oxidase complex genes that do not cause CGD are associated with the development of inflammatory bowel disease (IBD).
Methods
Direct sequencing and candidate gene approaches were used to identify susceptibility loci in NADPH oxidase complex genes. Functional studies were carried out on identified variants. Novel findings were replicated in independent cohorts.
Results
Sequence analysis identified a novel missense variant in the neutrophil cytosolic factor 2 (NCF2) gene that is associated with very early onset IBD (VEO-IBD) and subsequently found in 4% of patients with VEO-IBD compared with 0.2% of controls (p=1.3×10−5, OR 23.8 (95% CI 3.9 to 142.5); Fisher exact test). This variant reduced binding of the NCF2 gene product p67phox to RAC2. This study found a novel genetic association of RAC2 with Crohn's disease (CD) and replicated the previously reported association of NCF4 with ileal CD.
Conclusion
These studies suggest that the rare novel p67phox variant results in partial inhibition of oxidase function and are associated with CD in a subgroup of patients with VEO-IBD; and suggest that components of the NADPH oxidase complex are associated with CD.
doi:10.1136/gutjnl-2011-300078
PMCID: PMC3806486  PMID: 21900546
25.  Pilot Genome Wide Association Search Identifies Potential loci for Risk of Erectile Dysfunction in Type 1 Diabetes Using the DCCT/EDIC Study Cohort 
The Journal of urology  2012;188(2):514-520.
Purpose
To identify genetic predictors of diabetes-associated ED using genome wide and candidate gene approaches in a cohort of men with type I diabetes.
Methods
We examined 528 white men with T1D (125 with ED) from the DCCT and its observational follow up EDIC Study. ED was defined from a single item of the IIEF. An Illumina Human1M BeadChip was used for genotyping. 867,125 single nucleotide polymorphisms (SNPs) were subjected to analysis. Whole genome and candidate gene approaches tested the hypothesis that genetic polymorphisms may predispose men with T1D to ED. Univariate and multivariate models were used controlling for age, HbA1c, diabetes duration, and prior randomization to intensive or conventional insulin therapy during DCCT. A stratified false discovery rate was used to perform the candidate gene approach.
Results
Two SNPs located on chromosome 3 in one genomic loci were associated with ED with p < 1×10−6. rs9810233 had a p-value of 7 × 10−7 and rs1920201 had a p-value of 9×10−7 The nearest gene to these two SNPs is ALCAM. The genetic association results at these loci were similar in univariate and multivariate analysis. No candidate genes met criteria for statistical significance.
Conclusions
Two SNPs, rs9810233 and rs1920101, which are 25 kb apart, are both associated with ED, albeit not meeting the standard GWAS significance criteria of p < 5 × 10−8. Other studies with larger sample sizes will be required to determine whether ALCAM represents a novel gene in the pathogenesis of diabetes associated ED.
doi:10.1016/j.juro.2012.04.001
PMCID: PMC3764461  PMID: 22704111
Erectile Dysfunction; Diabetes; Genetics

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